On November 6, Alberto Gutierrez, the head of the office in charge of regulating in vitro diagnostics at FDA’s Center for Devices and Radiological Health (CDRH), discussed the two Laboratory-Developed Test (LDT) draft guidances with members of a federal advisory committee devoted to laboratory issues. (We previously reported on the draft guidances, which FDA released on October 3, here and here). Dr. Gutierrez fielded several questions from the advisory panel members, and –even though he was interrupted by fire alarms–provided some additional insights on how the agency plans to regulate LDTs, although a plethora of questions remain to be answered.

Dr. Gutierrez, Director, Office of In Vitro Diagnostics and Radiological Health (OIR), at CDRH, discussed the draft guidances during the second day of the November 5-6 Clinical Laboratory Improvement Advisory Committee (CLIAC) meeting in Atlanta, Georgia. CLIAC, which is managed by the Centers for Disease Control and Prevention (CDC), provides scientific and technical advice and guidance to the Department of Health and Human Services (HHS) related to laboratory issues. The CLIAC discussion comes on the heels of an October 23 FDA webinar on the topic (previously blogged on here).

Key points include:

No Premarket Review Grace Period for New Highest-Risk LDTs Introduced after Final Guidance Issued. Dr. Gutierrez stated that the need for premarket review for new LDTs that fall into the highest-risk category goes into effect the moment the final LDT guidance is published. Those highest-risk category tests are LDTs with the same intended use as cleared/approved companion diagnostics, LDTs with the same intended use as approved Class III medical devices, and certain LDTs for determining safety and effectiveness of blood or blood products. The draft guidance states that for the highest risk LDTs already on the market, the laboratory will have 12 months to submit an application. That statement implies that new LDTs would not receive a similar grace period. Dr. Gutierrez is now explicitly stating that LDTs that fall within the highest-risk category not on the market at the time the final guidance is issued will not receive a grace period from the premarket review requirements. The upshot is that if the LDT guidance goes into effect as written, laboratories will want to begin marketing their tests before the guidance is issued.

Determining Risk. FDA will publish a priority list for the timeframe for premarket submissions for the remaining high-risk LDTs in year two. FDA will publish a priority list for moderate-risk LDTs in year four. The agency will consult advisory panels to determine these priority lists. However, according to Dr. Gutierrez’s slides, FDA anticipates that after the highest-risk LDTs identified in the draft guidance, the next group of high-risk devices for which the agency will seek premarket submissions/applications include “devices that act like companion diagnostics; screening devices for serious diseases/conditions intended for use in asymptomatic patients without other confirmation; and diagnostics for certain infectious diseases with high-risk intended uses.”

In response to a question about how FDA would determine whether an LDT was high or moderate risk, Dr. Gutierrez stated that the risk depends on both the analyte and the intended use. For instance, with a biomarker for cancer, if the test is intended to screen asymptomatic patients to determine who has cancer, this would be a high-risk test because if there is a false negative, then the clinician will miss cancer. If there is a false positive, the patient will needlessly undergo medical procedures that may result in morbidity or mortality for the patient. The same biomarker for cancer monitoring is likely to be moderate risk, he suggested. Monitoring involves multiple longitudinal assessments, so a false result is less risky to the patient. Dr. Gutierrez also stated that only a small portion of IVD kits are Class III devices, and he expects that the same ratio will apply for LDTs.

LDTs Subject to Prohibition against False and Misleading Statements. Dr. Gutierrez indicated that even if an LDT already on the market is not subject to premarket review yet under the phased timeline, if the company makes a statement about the test that “is not credible,” FDA can immediately initiate enforcement action. Essentially, on the day the guidance takes effect, LDTs will be subject to the misbranding provision under Section 502(a) of the Federal Food, Drug, and Cosmetic Act, which prohibits false and misleading claims.

Notification. Dr. Gutierrez stated that the agency was considering having a link between the National Institutes of Health (NIH) registry of LDTs and FDA’s notification database, so that if a laboratory’s test already was registered with NIH, the laboratory would not have to duplicate that information, but would only need to complete a few fields where the information was not previously provided. He also said that the agency has yet to decide whether to make the FDA notification database public. He added he did not see any reason why it should not be public, as the agency can redact information such as information that could have public security implications. In response to questions about whether the agency should require notification for LDTs that meet the “Traditional” LDT category, Dr. Gutierrez noted that this was an area where the agency solicited specific comment and that the agency was “moving toward” not requiring notification for LDTs that fall into the Traditional LDT category.

Manufacturing Information. As to whether a laboratory submitting a PMA for a Class III LDT would need to include manufacturing information in the application, as is required for IVD kits, Dr. Gutierrez stated that the draft guidance as currently drafted does require such manufacturing information. However, Dr. Gutierrez stated that the agency is reconsidering this area. He noted that when the Quality System Regulation (QSR) went into effect in the 1990’s there was a phase-in period during which the inspections focused on education as opposed to enforcement. The agency is considering whether a similar approach would make sense here.

Will there be another draft guidance before a final guidance issues? Dr. Gutierrez said that whether there will be another draft guidance issued before a final guidance is issued will be justified “by the number of changes we make to” the current proposal. FDA issued two separate draft guidances when it was considering the In Vitro Diagnostic Multivariate Index Assay (IVDMIA) proposal. That proposal affected significantly fewer tests than this current proposal and was much less sweeping in scope and impact.

January 2015 Public Meeting. FDA will hold a two-day meeting in January 2015 to discuss the draft guidances.

CLIAC Deliberation of “Off-Label” Use of Waived Tests by Waived Laboratories. On November 5, panel members, FDA and Centers for Medicare & Medicaid Services (CMS) representatives extensively discussed the “off-label” use of waived tests by waived laboratories.

Under CLIA, a laboratory is either waived, moderate-complexity or high-complexity, with waived laboratories subject to the least amount of controls. Waived laboratories are not subject to routine inspections. A waived laboratory is only supposed to perform tests that are categorized by FDA as waived. These waived tests are supposed to be simple enough so that they can be performed reliably and accurately in these less sophisticated laboratories. We reported on FDA’s guidance on administrative procedures for categorization here.

Daralyn Hassan, a representative from CMS, explained that the majority of laboratories in the United States are waived. Specifically, 66 percent of CLIA laboratories possess a certificate of waiver. This represents a great increase, according to Ms. Hassan, from the 1990’s, when only around 20 percent of laboratories were waived. CMS initiated a pilot program in 2002 under which the agency had inspected two percent of the waived laboratories in all 50 states. The inspectors uncovered a number of problems in these waived laboratories during those inspections, which were announced before the inspector arrived. CMS found that, among other issues, multiple waived laboratories were performing waived tests for off-label uses. She said that devices used outside of the manufacturer’s requirements or intended use are considered to be test modification/off label use, and modified tests are no longer considered waived.

FDA representatives indicated that the way FDA is dealing with the issue is to seek more narrow indications for use. Prakash Rath, an OIR representative, said that FDA cleared indications for use are often broad, but the waived use is very narrow, and waived labs end up using the test for off-label populations or sample matrices. Dr. Rath added that “given the only control is labeling, FDA’s approach is to request clearance/approval within a narrow intended use that may include training.” He asked the committee to consider what else can be done to avoid the “off-label” use of waived tests by waived labs.

Dr. Gutierrez concurred that “where we are going to is narrower intended uses.” This conforms with our own recent experiences with OIR.

Dr. Gutierrez noted that while the agency considers labeling to be only control it has in waived testing, the labeling must be at a seventh-grade level. Given the requirement for a seventh-grade reading level, narrowing the intended use may not give the agency enough control over the waived testing: He is not certain the indications for use are well enough understood to provide a successful control in the waived setting.

CLIAC agreed to make two recommendations to HHS on the issue. First, CLIAC will recommend that the HHS facilitate development of a non-punitive and non-regulatory self-assessment checklist type tool and recommend it for use by all current CLIA-waived labs. The committee also recommended that CMS continue to consider potential changes to address this issue and report back to the committee on this issue.